1. Field of the Invention
The present invention relates to compounds having TGFβ inhibitory activity and more particularly to quinoline derivatives and quinazoline derivatives having TGFβ inhibitory activity. The present invention also relates to a pharmaceutical composition useful for the prophylaxis or therapy of diseases for which TGFβ inhibition is effective therapeutically.
2. Background Art
TGFβ (transforming growth factor-β) is a cytokine which is very important to organisms for regulating growth differentiation of cells and repair and regeneration of cells after tissue disorder. Disruption of its signal is known to cause onset and progression of various diseases.
The relationship between TGFβ and fibrosis of organs or tissues is well known. The fibrosis of an organ or a tissue takes place as a result of excessive accumulation of extracellular matrix proteins within the organ for repair or as a defence mechanism upon damage to the organ or the like by some cause. The extracellular matrix proteins refer to a substance surrounding cells of the tissue. For example, fibrotic proteins such as collagen and elastin, glycoconjugates such as proteoglycan, and glycoproteins such as fibronectin and laminin is included as major extracellular matrix proteins.
When the level of fibrosis of an organ is low, the organ can be recovered to a normal state without leaving any scar. On the other hand, when the level of lesion of the organ is large or when the lesion continues, the fibrosis causes damage to the innate function of the organ. Further, the damage causes new fibrosis to create a vicious cycle. Ultimately, this causes organ failure and, in the worst case, sometimes leads to death.
TGFβ is known to play an important role in the accumulation of the extracellular matrix proteins.
For example, the administration of TGFβ to normal animals is known to cause fibrosis in various tissues (International Review of Experimental Pathology, 34B: 43-67, 1993). Further, fibrosis of tissues is also observed in the TGFβ1-highly expressing transgenic mice, and in the normal animals transduced TGFβ1 gene locally (Proc. Natl. Acad. Sci. USA, 92: 2572-2576, 1995; Laboratory Investigation, 74: 991-1003, 1995).
TGFβ is considered to participate in the fibrosis of tissues through the following mechanism.
1) TGFβ strongly induces mRNA expression of extracellular matrix proteins such as fibronectin (Journal of Biological Chemistry, 262: 6443-6446, 1987), collagen (Proc. Natl. Acad. Sci. USA, 85 1105-1108, 1988), and proteoglycan (Journal of Biological Chemistry, 263: 3039-3045, 1988) in cells.
2) TGFβ lowers the expression of an extracellular degradative enzyme for extracellular matrix proteins (Journal of Biological Chemistry, 263: 16999-17005, 1988) and, in addition, highly promotes the expression of an inhibitor of the extracellular matrix degradative enzyme (Cancer Research, 49: 2553-2553, 1989). Consequently, the degradation of the extracellular matrix proteins is suppressed.
3) Further, TGFβ increases the expression of integrin as a receptor of extracellular matrix proteins and promotes the deposition of the extracellular matrix proteins around cells (Journal of Biological Chemistry, 263: 4586-4592, 1988).
4) Furthermore, TGFβ proliferates cells which produce extracellular matrix proteins, such as fibroblast cells (American Journal of Physiology, 264: F199-F205, 1993).
TGFβ is known to be mainly involved in the fibrosis of organs such as kidney, liver, lung, heart, bone marrow, and skin.
For example, the analysis of expression of TGFβ1 clearly demonstrate an increase in expression of TGFβ1 in diseases such as human acute renal diseases, chronic renal diseases, diabetic nephropathy, renal allograft rejection, HIV nephropathy, hepatic fibrosis, cirrhosis, pulmonary fibrosis, scleroderma, and keloid (New Engl. J. Med., 331, 1286-1292, 1994), and the correlation between the TGFb1 expression and the extracellular matrix protein expression.
Further, in pathologic aminal models, such as renal failure diseases, diabetic nephropathy, hepatic fibrosis, pulmonary fibrosis, and scleroderma, it is reported that the administration of soluble receptor comprising the extracellular region of type II receptor and TGFβ-neutralizing antibody can inhibit fibrosis and can improve the pathology (Nature, 346: 371-374, 1990; Journal of the British Thoracic Society, 54: 805-812, 1999; Journal of Immunology, 163: 5693-5699, 1999; Human Gene Therapy, 11: 33-42, 2000; Proc. Natl. Acad. Sci. USA., 97: 8015-20, 2000).
These facts show that the inhibition of TGFβ is useful for the prophylaxis and therapy against all diseases involving fibrosis including chronic renal diseases.
Further, TGFβ is also involved in restenosis and arteriosclerosis.
In restenosis model animals, an increase in expression of TGFβ1 and its receptor is observed in a injured blood vessel, and TGFβ1 is suggested to be involved in the formation of new intima after balloon injury is suggested (Clinical and Experimental Pharmacology and Physiology 23: 193-200, 1996).
In arteriosclerosis, a highly expression of TGFβ1 is observed in non-foam macrophage infiltrated in an affected region in which matrix proteins synthesis strongly takes place, (American Journal of Physiology 146: 1140-1149, 1995), suggesting that the non-foam macrophage participates in matrix protein synthesis in an arteriosclerosis affected region through TGFβ1.
Further, in a cell-migration test, TGFβ1 is also reported to be a potent stimulating factor for migration of smooth muscle cells causative of arteriosclerosis and vascular restenosis (Biochem Biophys Res Commun., 169: 725-729, 1990).
TGFβ1 is also involved in wound repair.
For example, an experiment using a neutralizing antibody against TGFβ1 demonstrates that the inhibition of TGFβ1 suppresses excessive scar after wound and is useful for functional recovery. Specifically, it is also known that the administration of a neutralizing antibody against TGFβ1 or TGFβ2 to rats can suppress scar and promotes dermal cell construction via a mechanism of the suppression of dermal fibronectin and collagen deposition and a reduction in the number of monocytes and macrophages (Journal of Cellular Science 108: 985-1002, 1995). In other tissues, the administration of anti-TGFβ neutralizing antibody improves lesions in a rabbit corneal injury model and a rat gastric ulcer model (Cornea 16: 177-187, 1997; An international Journal of gastroenterology & Hepatology 39: 172-175, 1996).
Further, TGFβ1 is also known to be involved in peritoneal adhesion.
For example, it is suggested that the inhibition of TGFβ is effective in suppressing peritoneal adhesion and subdermal fibrotic adhesion after surgery (J. Surg. Res., 65: 135-138, 1996). A number of articles report that the administration of an anti-TGFβ neutralizing antibody or a soluble type II TGFβ receptor to cancer disease model animals has also beneficial effects on suppression of tumor growth and cancer metastasis (Journal of Clinical Investigation, 92: 2569-76, 1993; Clinical Cancer Research 7: 2931-2940, 2001; Cancer Res. 59: 2210-6, 1999; Journal of Clinical Investigation 109: 1551-1559, 2002; Journal of Clinical Investigation 109: 1607-1615, 2002).
Tumors usually acquire tumor growth capability and metastatic capability by inducing angiogenesis on host side and by lowering immunity of the host side through TGFβ produced by the tumors per se. The suppression mechanism is based on the evidences that the administration of the anti-TGFβ neutralizing antibody suppress the tumor growth capability and metastatic capability. Thus, the inhibition of TGFβ is considered to be effective in suppressing cancer metastasis and cancer cell growth.
It is also reported that an anti-TGFβ1 neutralizing antibody is effective in in-vitro amplification of hematopoietic stem cells (Experimental Hematology 26: 374-381, 1998). Further, TGFβ1 has growth inhibitory activity against a large variety of cells. Accordingly, the inhibition of TGFβ is expected to be effective in in-vitro amplification of a large variety of cells including hematopoietic stem cells.